The long term objective of this project is to develop validated, genotype-based biomarkers to aid in more accurate diagnosis of schizophrenia and related schizophrenia spectrum disorders, including bipolar disorder. SureGene, LLC is developing two novel genetic tests, one based on the SULT4A1 gene on chromosome 22q (which is supported by a multipoint LOD score of 4.78, assuming genetic heterogeneity in NIMH family samples) and another involving proprietary genetic markers in conjunction with novel microdeletions elsewhere in the genome (odds ratio of approximately 15). These tests need to be further refined before they are ready for general clinical and research use. Additionally, SureGene plans to determine if chromosomal linkages called quantitative trait loci (QTL) that significantly affect behavioral variation in the human population can be used to define novel genes influencing diagnostic components of schizophrenia spectrum disorders. First, to test the hypothesis that chromosomal regions contributing to schizophrenia-related phenotypes in an unselected population contain one or more genes influencing susceptibility to spectrum disorders we will perform targeted microsatellite and single nucleotide polymorphism genotyping with NIMH schizophrenia and bipolar family samples and evaluate the results by linkage analyses and transmission disequilibrium testing. Second, we will determine the frequencies of putative susceptibility haplotypes for novel loci in populations of schizophrenia subjects, and control African American and European American populations, in order to get a more complete picture of the relative risks, or odds ratios, associated with these genetic tests. Finally we will analyze the molecular nature of a targeted set of putative susceptibility alleles. Using quantitative polymerase chain reaction methods, we will find the end points of the novel deletions and describe the region of overlap. Also, we will perform targeted resequencing of novel positional candidate genes with the goal of better understanding the molecular mechanisms contributing to increased risk. We anticipate that intellectual property (IP) will come out of the proposed research in the form of genotype-based diagnostic products and services. Such products should be helpful to individuals suffering from schizophrenia and related disorders, their families and health care providers, and researchers seeking to improve diagnosis and treatment. [unreadable] [unreadable] [unreadable]